epoetin alfa




Full Prescribing Info
Epoetin alfa.
Eprex is a sterile, clear, colorless, preservative-free solution for IV or SC injection. It is formulated in a 0.25% buffered human serum albumin solution. The pH of the solution is 6.7-7.3.
Eprex has the highest possible purity according to the present state of the art. No residues of the cell line used for production are detectable at the concentrations of the active ingredient used in humans.
Epoetin alfa is a glycoprotein that is produced by recombinant DNA technology.
Pharmacology: Erythropoietin is an endogenous glycoprotein hormone that regulates red blood cell production. Its production primarily occurs in and is regulated by the kidney in response to changes in tissue oxygenation.
Recombinant-human erythropoietin (r-HuEPO) stimulates the proliferation, maturation and differentiation of erythroid precursors in the bone marrow in a manner identical to that of endogenous human erythropoietin. R-HuEPO has been shown to stimulate erythropoiesis in normal volunteers, chronic renal failure (CRF) patients and in HIV-infected patients with endogenous erythropoietin levels <500 mU/mL by IV and SC administration with the erythropoietic response being dose-related.
Pharmacokinetics: Measurement of r-HuEPO following IV administration revealed a half-life of approximately 4 hrs in normal volunteers and a somewhat more prolonged half-life in renal failure patients (7-8 hrs).
After SC dosing with r-HuEPO in normal volunteers, peak serum levels are achieved 5-24 hrs after dosing and decline slowly thereafter. The area under the curve (AUC) after single SC dosing is approximately 15% of the AUC after IV dosing. Despite the pharmacokinetic differences between IV and SC administration of r-HuEPO, information available to date suggests that the effect of exogenous hormone on hematologic parameters is not significantly different between the 2 routes of administration.
No r-HuEPO-binding antibodies have been detected in >1000 patients treated.
Treatment of symptomatic or transfusion-requiring anemia associated with chronic renal failure. Reduction of red blood cell transfusion requirements in azidothymidine (AZT)-treated HIV-infected patients with inappropriately low endogenous r-HuEPO levels.
Dosage/Direction for Use
Anemia or Chronic Renal Failure: Recommended Starting Dose: 50 units/kg, 3 times/week, administered as IV injection over 1-2 min or SC injection.
Dose adjustments should depend upon the initial response on hemoglobin levels (proposed rate <2 g/dL/month). If required, dose increments in steps of 25 units/kg/dose in intervals of 4 weeks are recommended.
If the rate of hemoglobin rise exceeds 2 g/dL/month at 50 units/kg, 3 times/week, downward dosage adjustments should be made in the amount administered in each dose and by omitting one of the weekly doses. Similar downward dose adjustments should be made if the Hb level exceeds 12 g/dL.
Maximum dose should generally not exceed 200 units/kg 3 times/week.
When Hb level of 10-12 g/dL (HCT 30-35%) has been achieved, the total maintenance weekly dose (average 100-300 units/kg) can be apportioned in 2 or 3 injections. The optimal level of Hb is left to the discretion of the physician, however, 10-12 g/dL has been shown to be well tolerated. Available data indicate that patients starting treatment at very low Hb levels (<6 g/dL) may require higher maintenance dosages than those starting therapy with Hb >8 g/dL; the latter group of patients may need weekly doses as low as 100 units/kg.
Iron status should be evaluated for all patients prior to and during treatment and iron supplementation administered if necessary. Non-response to r-HuEPO therapy should prompt a search for causative factors. These include iron, folate or vitamin B12 deficiency; aluminum intoxication; intercurrent infections, inflammatory or traumatic episodes; occult blood loss; hemolysis; and bone marrow fibrosis of any origin.
In patients maintained on hemodialysis, r-HuEPO should always be administered after completion of dialysis.
Reduction or elimination of transfusion requirements in AZT-treated HIV-infected patients.
Prior to initiating therapy with r-HuEPO, it is recommended that endogenous serum erythropoietin is measured. It is unlikely that patients with endogenous serum erythropoietin levels >500 mU/mL will respond to r-HuEPO therapy.
The initial dose of r-HuEPO should be 150 units/kg by IV bolus or SC injection injected 3 times/week. In case of an adequate response to treatment, the dose can be escalated in a stepwise fashion to a maximum of about 500 units/kg IV or SC 3 times/week.
Administration: Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration.
Use the graduated pre-filled syringe.
Administer as IV or SC injection over 1-2 min. In patients on hemodialysis, the injection should be performed after the dialysis procedure. Slow IV or SC injection over 5 min SC injection may be preferred in those patients who experience flu-like symptoms.
Do not administer by IV infusion or in conjunction with other drug solutions.
Response to r-HuEPO is dose-related and individualized. In case of an excessive erythropoietic response from an overdose of r-HuEPO, dosing should be stopped and phlebotomy can be considered. Supportive care should be provided for hypertensive or convulsive events that may be related to overdosing with r-HuEPO (see Warnings).
There are no known contraindications.
Anemia of Chronic Renal Failure: If hypertension develops, fluid overload should be excluded and treatment with antihypertensive drugs, preferably peripheral vasodilators, should be prescribed before reduction of dry weight. Reduction of dry weight may lead to a further rise in hematocrit and viscosity.
Phlebotomy may be considered in individual patients, especially if the Hb is >12 g/dL or has risen in excess of 2 g/dL/month. If an episode of acute hypertension occurs with or without encephalopathy, r-HuEPO should be stopped (Hb concentration will subsequently decrease by approximately 0.4 g/dL weekly).
EEG and CT-scan are considered useful to rule out causes of seizures and may be performed and repeated as necessary. r-HuEPO should be re-introduced only with close monitoring of Hb and blood pressure until the Hb is stabilized in the range of 10-12 g/dL.
AZT-Treated HIV-Infected Patients: There is no evidence to suggest that r-HuEPO therapy is associated with an increased incidence or risk of hypertension in AZT-treated HIV-infected patients.
Seizures have been reported in AZT-treated HIV-infected patients treated with r-HuEPO, but were probably related to underlying pathology eg, meningitis or cerebral neoplasms.
Two HIV-infected patients had urticarial reactions within 48 hrs of their first exposure to study medication. One patient was treated with r-HuEPO alone and one patient with vehicle solution alone. Both patients had positive immediate skin tests against their study medication. The basis for this apparent preexisting hypersensitivity to components of the r-HuEPO formulation is unknown, but may be related to HIV-induced immunosuppression and prior exposure to blood products.
Special Precautions
r-HuEPO should be used with caution in those patients with uncontrolled hypertension, ischemic vascular disease, history of seizures or suspected allergy to any components of Eprex.
CRF patients should be closely monitored for changes in hemoglobin, blood pressure and serum electrolytes, because preliminary evidence suggests that hypertensive episodes (in some cases associated with hypertensive encephalopathy and seizures) are most likely to occur in patients experiencing a rapid Hb response. An increase in Hb of <2 g/dL/month is recommended. If blood pressure begins to increase or, is accompanied by headache, more aggressive antihypertensive treatment should be used. In cases where the rise in blood pressure is difficult to control, the patients should be admitted to the hospital or clinic for observation until their blood pressure is adequately controlled. No such problems with accelerated high blood pressure have been observed in AIDS patients.
At the start, all patients on r-HuEPO should have their hemoglobin levels measured no less than weekly until a stable level of 10-12 g/dL is achieved and periodically monitored thereafter.
Correction of anemia may result in increased appetite and potassium intake which in turn could lead to hyperkalemia in both dialysis and predialysis patients.
Moreover, correction of anemia in dialysis patients may result in decreased dialysis efficiency resulting in increased predialysis serum potassium, creatinine and inorganic phosphorus. These alterations in serum chemistry should be managed by dietary alterations and modifications of the dialysis prescription if appropriate.
In some preclinical toxicological studies in dogs and rats, but not in monkeys, r-HuEPO therapy was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of chronic renal failure in humans and may be related to secondary hyperparathyroidism or unknown factors. The incidence of bone marrow fibrosis was not increased in a study of dialysis patients who were treated with r-HuEPO for 12-19 months compared to the incidence of bone marrow fibrosis in a matched control group of dialysis patients who had not been treated with r-HuEPO.
Based on information available to date, correction of anemia with r-HuEPO in predialysis patients does not accelerate the rate of progression of renal insufficiency.
The dialyzer should be monitored for evidence of increased clotting, and if present, an increase in dialysis heparin may be required.
In very exceptional cases, r-HuEPO therapy has been associated with exacerbation of porphyria in CRF patients. However, r-HuEPO has not caused increased urinary excretion of porphyrin metabolites in normal volunteers, even in the presence of a rapid erythropoietic response. Nevertheless, r-HuEPO should be used with caution in patients with known porphyria.
Increased serum uric acid and gouty episodes may occur in predisposed patients whose hemoglobin is rising by approximately >2 g/dL/month.
Use in children: Safety and efficacy in children have not been definitely established.
Use In Pregnancy & Lactation
R-HuEPO should be administered during pregnancy and lactation only if clearly needed. It is not known whether it can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity.
Adverse Reactions
The following adverse events have been observed in hemodialyzed patients treated with r-HuEPO: Increased blood pressure 28.6%; thrombosis of vascular access sites eg, fistula 13%; flu-like symptoms, bone pain and chills following injections 7.6%; seizures 4.3%; skin reactions, palpebral edema, possibly allergic in nature 2.2%.
The following adverse events have been observed to occur in predialysis patients treated with r-HuEPO more frequently than in predialysis patients treated with placebo: Hypertension; headache; arthralgia; pyrexia.
No adverse events have been observed in AIDS patients treated with r-HuEPO more frequently than in AIDS patients treated with placebo.
Drug Interactions
There are no known clinically significant drug interactions, but the effect of r-HuEPO may be restored by the simultaneous therapeutic administration of a hematinic agent eg, ferrous sulfate when a deficiency state exists.
Caution For Usage
Parenteral drug product should be visually inspected for particulate matter and discoloration prior to administration.
Do not administer by IV infusion or in conjunction with other drug solutions.
Store at 2-8°C. Do not freeze or shake. Protect from light.
Shelf-Life: 18 months.
ATC Classification
B03XA02 - darbepoetin alfa ; Belongs to the class of other antianemic preparations. Used in the treatment of anemia.
Pre-filled syringe with needle guard 2000 IU/0.5 mL x 1's. 4000 IU/0.4 mL x 1's. 10,000 IU/mL x 1's.
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